Vaccines are perhaps one of the most successful medical interventions against infectious disease. An important component in the design of effective vaccines is the incorporation of appropriate immune potentiators (also termed adjuvants) along with the antigen; adjuvants initiate early innate immune responses, which lead to the induction of robust and long-lasting adaptive immune responses. More than eight decades have elapsed since the discovery of adjuvanticity of aluminum salts (primarily phosphate and hydroxide) and the repertoire of investigational adjuvants has grown to encompass a very wide range of materials; however, aluminum salt-based mineral salts (generically, and incorrectly, termed “alum”) have, until the recent introduction of 3-O-desacyl-4′-monophosphoryl lipid A (MPL), remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record but are weak adjuvants for antibody induction, promoting a TH2-skewed, rather than a TH1 response. Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses but also have an undesirable propensity to induce IgE isotype switching, which has been associated with allergic reactions in some subjects (Relyveld, E. H., et al. Vaccine 1998, 16, 1016-1023; Gupta, R. K. Adv. Drug Delivery Rev. 1998, 32, 155-172).
Toll-like receptors (TLRs) are pattern recognition receptors present on diverse cell types. TLRs recognize specific molecular patterns present in molecules that are broadly shared by pathogens but are sufficiently different so as to be distinguishable from host molecules and are collectively referred to as pathogen-associated molecular patterns (PAMPs). There are 10 TLRs in the human genome; these are transmembrane proteins with an extracellular domain having leucine-rich repeats (LRR) and a cytosolic domain called the Toll/IL-1 receptor (TIR) domain (Kumagai, Y. et al. J. Infect. Chemother. 2008, 14, 86-92).
The ligands for these receptors are highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single-stranded RNA (TLR7 and TLR8), double-stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR 11) (Kumagai, Y. et al J. Infect. Chemother. 2008, 14, 86-92; Takeda, K. Akira, S. Curr. Protoc. Immunol. 2007, Chapter 14, Unit 14, p 12). TLR1, -2, -4, -5, and -6 respond to extracellular stimuli, while TLR3, -7, -8, and -9 respond to intracytoplasmic PAMPs, being associated with the endolysosomal compartment (Kumagai, Y. et al. Infect. Chemother. 2008, 14, 86-92). The activation of TLRs by their cognate ligands leads to production of inflammatory cytokines, and up-regulation of MHC molecules and costimulatory signals in antigen-presenting cells as well as activating natural killer (NK) cells (innate immune response), in addition to priming and amplifying T- and B-cell effector functions (adaptive immune responses) (Akira, S. Adv. Immunol. 1902, 78, 1-56; Akira, S. et al. Nature Immunol. 2001, 2, 675-680; Cottalorda, A. et al. Eur. J. Immunol. 2006, 36, 1684-1693; Kaisho, T. et al. Biochim. Biophys. Acta 2002, 1589, 1-13).